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Abstract

Several recent papers, including one in BMC Evolutionary Biology, examine the colonization history of house mice. As well as background for the analysis
of mouse adaptation, such studies offer a perspective on the history of movements
of the humans that accidentally transported the mice.

Commentary

Commensals of humans are likely to share the human global distribution. Being easily
noticed, and surviving and reproducing well in environments that humans create, they
also include some of the most favored model organisms. A prime example of this is
the house mouse, Mus musculus, which is both the 'classic' mammalian model organism and a globally present commensal.
Through its association with humans, the house mouse is even found in the remotest
archipelagos, such as Kerguelen, a group of sub-Antarctic islands with a mean summer
temperature as low as 8°C. It is the mouse populations inhabiting this inhospitable
place that are the focus of a study by Hardouin et al. in BMC Evolutionary Biology[1].

With all the genomic tools available, there is currently a scramble to study the genetics
of adaptation in house mice. What better place to study that than Kerguelen? Here,
human occupancy is restricted to the few inhabitants of a research station on the
main island (Grande Terre). The mice on these islands live outdoors in extreme conditions
and, in contrast to the typical seed-eating of house mice elsewhere, they feed primarily
on invertebrates. To understand the adaptations for this exceptional lifestyle, it
is important to know something about the history of the mice. In particular: where
did the mice come from? Is it a genetically mixed population? Is the population young
or old? Hardouin et al. [1] investigated all these questions for Kerguelen house mice which belong to the western
subspecies, Mus musculus domesticus.

The Kerguelen study

Hardouin et al.'s study [1] involved 437 mice from Kerguelen, an unprecedented coverage for the analysis of colonization
history of such a small area. They found remarkable consistency in the mitochondrial
DNA (mtDNA) sequences on Grande Terre and most of the surrounding small islands, suggesting
that these populations are the product of a single relatively recent colonization
(ultimately deriving from Europe). This fits with the recorded discovery of the archipelago
in 1772 (by a Frenchman called Kerguelen-Trémarec) and settlement by mice either at
the time or with subsequent human arrivals. Two of the other small islands in the
archipelago (Cochons and Cimetière) may have been colonized in a second, separate
introduction, as their mice belong to a different mtDNA lineage (also ultimately European).
Over the archipelago as a whole there was no evidence of within-island heterogeneity
in terms of mtDNA lineage. This is surprising given the large number of ships carrying
mice that would have visited the islands (coming from many different places and therefore
carrying mice of many different mtDNA lineages). These results are consistent with
other data [2] suggesting that mouse populations are resistant to secondary invasion by females
(mtDNA is a maternally inherited marker). Presumably, newly arriving females coming
into an established population are generally unable to survive or gain mates, and
in consequence do not contribute to the population's gene pool. All of this means
that mtDNA may be a very good marker for initial colonization by house mice within
a given area.

Studies on European mice

The association of Mus musculus domesticus with humans in a European context has long been studied by zooarcheologists, and
genomic tools are now being deployed to study adaptation in some of these European
populations. With regard to colonization history, there is much zooarcheological evidence
on the progression of mice from their site of first commensalism with humans in the
Near East through the Mediterranean region, providing a good test on the match between
mtDNA sequences and the historical record. Gratifyingly, Bonhomme et al. [3] have identified a discontinuity in mtDNA lineages that fits very well with the two
phases of mouse colonization of the Mediterranean revealed by zooarcheologists (Figure
1). The eastern Mediterranean was colonized by mice during the Neolithic when they
were first able to exploit stored grain. However, the western Mediterranean could
not be colonized by house mice until the Iron Age (Figure 1), when settlements reached a sufficient size for the house mice not to be outcompeted
by local mice living outdoors, and when seafarers such as the Phoenicians carried
cargoes of sufficiently large size to inadvertently transport house mice [3,4].

Figure 1.Maps showing possible colonization routes taken by the western house mouse Mus musculus domesticus, based on mtDNA evidence. Neolithic (starting 12,000 years ago): colonization restricted to the eastern Mediterranean
close to where this subspecies first became commensal [3]. Iron Age (starting 3,000 years ago): colonization westwards along the Mediterranean
and then into north-west Europe by overland and coastal routes [3,5]. Viking Age (around 1,000 years ago): movements around the periphery of north-west
Europe and colonization of Scandinavia and Madeira [2,5,7,8]. (The colonization of Scandinavia may have been earlier [7].) Recent history (a few hundred years ago): mice were taken substantial distances
from western Europe, including to Kerguelen [1]. The dashed line shows the location of the hybrid zone between the subspecies M.
m. domesticus and M. m. musculus.

Studies by ourselves and others have looked at the mtDNA lineages of house mice in
northern Europe. A different lineage from those typically seen in Mediterranean Europe
has been found further north in the area between Britain and Germany [2,5]. The mouse mtDNA again matches a regional sphere of influence of Iron Age people
[6], and, unlike other mouse mtDNA lineages, it appears that this Anglo-German lineage
did not arrive in northern Europe by an overland route; instead it probably came along
the Atlantic coast (Figure 1).

mtDNA studies suggest another pulse of detectable mouse colonizations during Viking
times (Figure 1). Like the Phoenicians, the Vikings were impressive seafarers, carrying substantial
cargoes ideal for stowaway mice, and there are mtDNA signals of maritime colonization
events [2,5,7,8].

How did Mus musculus domesticus get from Europe to Kerguelen? This subspecies had been in the right place at the
right time to make use of the first storage of grain by Neolithic humans in the Fertile
Crescent in the Middle East, and to adapt to changing human cultural practices. Good
fortune struck again when the subspecies found itself in western Europe at the time
that British, Dutch, French and Iberian seafarers were 'discovering', exploiting and
taking settlers to the rest of the world. Kerguelen-Trémarec and his crew may have
been the first humans to see the archipelago that now bears his name, but the colonization
route of the first mice to arrive there is still uncertain, although their starting
point was certainly western Europe (Figure 1).

Mice as a proxy for human history

It is intriguing how far the linkage between human history and mouse history may go.
Jones et al. [8] found a correlation between mouse genetic diversity and human population size (proportional
to amount of mouse habitat) in discrete areas of the Faroe Islands in the northeastern
Atlantic Ocean, another archipelago where house mice have been studied. This supports
the expectation that the population genetics (in terms of genetic response to population
expansions and contractions) of house mice is likely to reflect rather closely the
population genetics of humans.

We have been considering how the history of humans impacts on the genetics of the
house mouse, but that can be turned around. If the history of house mice is so intimately
determined by humans, then the genetics of house mice may be useful to answer human
historical questions; for example, the details of human affiliations in the Iron Age
are sometimes imprecise - might house mice be able to indicate associations between
Iron Age people from different geographical areas? House mice are equivalent to an
artifact that an archeologist discovers and uses to determine human colonization or
trading routes. The provenance of the mice is established from their DNA sequence
and that is a very powerful tool, given its extraordinary information content. Not
only can the DNA sequence help to establish the source of the mice found in a particular
place but it can be used to date the original colonization and subsequent population
history (including secondary colonizations), following approaches used for human DNA
(see, for example [9])). However, it is clear from all the recent papers considered here [1,3,5,7,8] that archeogenetics using house mice is at an early stage, and that, in particular,
calibrations to generate an accurate mouse mtDNA molecular clock are urgently needed.
Hardouin et al. [1] comment that, for the mtDNA region analyzed, they found a much higher mutation rate
than suggested by previous studies. Further work should follow up this finding and
also use other subspecies to globalize the opportunities for applying mice as a proxy
to study humans, following the lead of another recent paper [10].

Acknowledgements

SIG was funded by the scholarship SFRH/BD/21437/2005 from Fundação para a Ciência
e a Tecnologia (Portugal), FJ and JBS by Cornell University (USA) and EPJ by the Carl
Trygger Foundation (Sweden). We are grateful to Angela Douglas for her comments on
the manuscript.